ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.3392C>T (p.Thr1131Ile) (rs199473197)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183033 SCV000235441 uncertain significance not specified 2016-06-24 criteria provided, single submitter clinical testing The T1131I variant of uncertain significance in the SCN5A gene was originally reported in an African Americanindividual who was diagnosed with atrial fibrillation in conjunction with underlying structural heart disease at age 42(Darbar et al., 2008). In a subsequent analysis of 274 sudden unexplained death cases with negative autopsy findings,T1131I was reported in one African American infant who died at two weeks of age while co-sleeping (Wang et al.,2014). The T1131I variant has also been identified independently and/or in conjunction with additional cardiogeneticvariants in individuals referred for cardiomyopathy/arrhythmia genetic testing at GeneDx; however, segregation data islimited or absent for these individuals due to the lack of clinical information provided and/or insufficient participationby informative family members. The T1131I variant was absent in 720 published control alleles of matched ethnicbackgrounds (Darbar et al., 2008), and was not observed with any significant frequency in approximately 6,400individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The T1131I variantis a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residuesdiffer in polarity, charge, size and/or other properties. Nevertheless, this substitution occurs at a position that is notconserved. Consequently, in silico analysis predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000468996 SCV000545083 uncertain significance Brugada syndrome 2020-06-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1131 of the SCN5A protein (p.Thr1131Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs199473197, ExAC 0.04%). This variant has been reported in an individual affected with atrial fibrillation who also presented with left atrial and left ventricular enlargements and in a case of sudden infant death (PMID: 18378609, 24631775). ClinVar contains an entry for this variant (Variation ID: 67795). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587127 SCV000700032 uncertain significance not provided 2017-07-02 criteria provided, single submitter clinical testing Variant summary: The c.3392C>T (p.Thr1131Ile) in SCN5A gene is a missense change that involves a non-conserved nucleotide resulting in a non-conservative amino acid substitution located within the cytoplasmic loop between domains II-III. 4/5 in silico tools predict benign, although at least one functional study have shown deleterious effect on the protein function, suggesting a potential causative reason for atrial fibrillation (AF) (Wang, 2010). However, this study has yet to be published in peer-reviewed journal at this time of this review therefore the evidence cannot be unequivocally considered. The variant is present in the large control population dataset of ExAC at a frequency of 4.455e-05 (4/89792 chrs tested), predominantly in individuals of African descent (0.000417; 3/7194 chrs tested). The variant has also been identified in gnomAD dataset at similar frequencies (0.00003; 8/267102 chrs tested). The observed frequency in African cohort exceeds the maximal expected frequency of a pathogenic allele (0.00016) in this gene. However, since no clinical information on ExAC participants are available, the possibility of them being a silent carrier of deleterious variant cannot be ruled out. In addition, the variant was reported in two patients presented with AF and SIDS. Both cases were reported to be of African descent. Since no segregation analysis was done for these patients, there are not enough evidence to classify this variant with confidence. Lastly, the c.3392C>T is cites as VUS by several reputable databases/clinical laboratories. Taking all line of evidence into consideration, the variant was classified as VUS until more information becomes available.
Color Health, Inc RCV001189178 SCV001356413 uncertain significance Arrhythmia 2019-04-30 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058569 SCV000090089 not provided Atrial fibrillation no assertion provided literature only This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:18378609). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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